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PXD038364

PXD038364 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleMonitoring α-synuclein ubiquitination dynamics reveals key endosomal effectors mediating its trafficking and degradation
DescriptionWhile defective α-synuclein homeostasis is central to the pathogenesis of Parkinson’s, fundamental questions about its intracellular trafficking remain unresolved. We have developed a bimolecular fluorescence complementation assay in living cells to monitor de novo ubiquitination of α-synuclein. We identified lysine residues 45, 58 and 60 as critical ubiquitination sites for the degradation of α-synuclein. This is mediated by NBR1 binding to ubiquitinated α-synuclein and entry into endosomes in a process that involves ESCRT I-III complexes for subsequent lysosomal degradation. Autophagy or the autophagic chaperone Hsc70 are dispensable for this pathway. Antibodies against diglycine-modified α-synuclein peptides confirmed that endogenous α-synuclein is similarly ubiquitinated in brain and targeted to the lysosome in rat primary and human iPSC-derived neurons. Ubiquitinated α-synuclein was detected in Lewy bodies and cellular models of aggregation suggesting that it may be entrapped with endo/lysosomes in inclusion bodies. Collectively, our data elucidate the intracellular trafficking of de novo ubiquitinated α-synuclein and provide the tools for investigating the rapidly turned-over fraction of this disease-causing protein.
HostingRepositoryPRIDE
AnnounceDate2023-05-17
AnnouncementXMLSubmission_2023-05-17_06:49:55.850.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterRomanFischer
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListubiquitinylated lysine
InstrumentOrbitrap Fusion Lumos; Q Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-11-25 07:02:48ID requested
12023-05-17 06:49:56announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Ubiquitination, degradation, Parkinson's, homeostasis,α-synuclein
Contact List
RomanFicher
contact affiliationDiscovery Proteomics Facility Target Discovery Institute University of Oxford
contact emailroman.fischer@ndm.ox.ac.uk
lab head
RomanFischer
contact affiliationUniversity of Oxford
contact emailroman.fischer@ndm.ox.ac.uk
dataset submitter
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Dataset FTP location
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